Project Summary/Abstract Tau-related neurodegenerative diseases represent a broad class of diseases all with underlying pathology of tau protein aggregation1. The spread of tau aggregation throughout the brain correlates with cognitive decline in patients and is thought to be essential for disease progression2. In addition to tau pathology, the ability of innate immune cells in the brain, particularly microglia and astrocytes, to mediate neuroinflammation has been implicated as a significant contributor to disease pathogenesis. Unfortunately, a detailed understanding of how tau spread is achieved in the central nervous system (CNS) and how this alters cross-talk between glia and neuronal cells is still not known. In Phase I (K99) of this grant proposal we will demystify the mechanisms that allow tau spread and uncover how cellular identity dictates response to tau insult. Preliminary work has identified a novel tau receptor that can mediate tau uptake and has allowed us to develop testable hypotheses about differential tau recognition between neurons and glia. Single cell RNA-sequencing experiments will allow us to uncover the transcriptional profiles generated under tau spread conditions and will push our understanding of how pathology is influenced by cellular identity. Following Phase I (R00), I will expand on methodology achieved during my mentorship and focus my research on questions related to microglial tau regulation and cellular influences on tau?s physical state. The novel experimental methods and comprehensive analyses outlined herein will develop our understanding of pathogenic tau regulation. Further, with this mechanistic insight we will be able to envision novel therapeutic strategies to block tau spread and aggregation.